ATP-sensitive K+ channels (KATP) couple the intermediary metabolism to cellular excitability, and play an important role in reactive hyperemia. It is known that hyperemia underlies the cardio-protective effect of ischemic preconditioning and the activity-dependent auto-regulation of cerebral circulation, and involves sensing of O2, CO2 and pH. Our recent studies indicate that KATP channels are indeed activated with high COz / low pH. The regulation of KATP by protons is significant, because a drop in pH levels often accompanies various metabolic stresses and is more frequently seen than sole energy depletion. Such regulation may enable cells to change their membrane excitability in response to a wide variety of physiologic and pathophysiologic conditions. However, previous studies on the pH sensitivity were rather controversial: proton was shown to stimulate cell-endogenous KATP in some studies but inhibit it in others. The inconsistence is further complicated by the indirect effect of ATP, ADP and Mg ++ on channel activity. Thereby, it is unclear how the KATP is modulated during hypercapnia and acidosis, whether these channels are inherently pH-sensitive, and what the molecular mechanisms underlying the modulation are. The cloned KATP channels are ideal for addressing these questions, which allow a fine dissection of the modulatory mechanisms and elaborate manipulations of PCO2 and pH in the expression system. Thereby, we have been studying the pH sensitivity of the cloned KATP over the past 3 years. Our preliminary data have clearly shown that proton is a potent activator of the KATP. TO further these observations, we have proposed studies aimed at 1) elucidating the modulation of KATP by hypercapnia and acidosis, 2) demonstrating the sensing mechanisms in the channel proteins, 3) determining factors and their interactions with protons in regulating the pH sensitivity, and 4) identifying the pH-sensitive KATP isoforms in vascular smooth muscles. This information should have profound impacts not only on cardiovascular physiology but also on the design of therapeutical modalities by manipulating the pH-sensing mechanisms to control cellular activity in stroke, epilepsy and coronary heart disease.